ABSTRACT Nutritional chemoprevention is a promising approach for combating prostate cancer (PCa). Pterostilbene (PTER), a naturally occurring dimethoxy analog of resveratrol found in blueberries and grapes, has more potent pharmacokinetic properties defined by greater bioavailability and effective tissue distribution due to its longer half-life, reduced metabolic rate, lipophilicity and cell membrane-permeability. Therefore, PTER presents stronger candidacy for successful clinical development. We propose PTER as a lead natural agent for PCa chemoprevention. We have compelling evidence that PTER regulates at least two epigenetic networks in PCa: the epigenetic modifier MTA1 and microRNAs that target or are modulated by epigenetic regulators (Epi-miRNAs). Metastasis-associated protein 1 (MTA1) plays an important role in PCa by participating in chromatin remodeling and transcriptional regulation. Although MTA1 is known to be closely associated with aggressive PCa, we have evidence of MTA1 involvement in the early inflammation-related carcinogenic events leading to development of PCa, which presents MTA1 as a new chemopreventive target. Moreover, we found that dietary PTER is a potent inhibitor of MTA1 and MTA1-guided signaling. This study will test the hypothesis that PTER may prevent development of PCa, at least in part, through its ability to directly block MTA1 -mediated gene regulation and to modulate MTA1-associated Epi-miRNAs. Inhibiting MTA1-guided signaling could effectively delay and/or prevent the development and progression of PCa. We propose to: (1) Evaluate the MTA1-mediated chemopreventive efficacy of PTER in PCa mouse models. (2) Determine the mechanistic role of MTA1 as a transcriptional regulator in PCa. (3) Determine the role of PTER-regulated MTA1-associated Epi-miRs as chemopreventive and predictive biomarkers. The successful completion of this study will aid in the development of much needed preventive strategies based on natural epigenetic agents for the effective management of PCa. In the future, innovative therapeutic strategies can be developed including combination of stilbenes and other MTA1 inhibitors. Results of this study will also provide novel information on whether Epi-miRs could be developed as prognostic and predictive biomarkers of early stage PCa. Moreover, the results of our study will provide sound foundation for clinical trials, after which they can immediately be translated to the clinic for PCa chemoprevention with a major impact upon thousands of men at high risk. Finally, this R15 application offers excellent research exposure opportunities for undergraduate, professional pharmacy, and graduate students and will undeniably make significant contributions to the expansion of the Arnold &Marie Schwartz College of Pharmacy and Health Sciences research enterprise.